Maple syrup urine disease (MSUD) is a rare inborn error of metabolism caused by impaired catabolism of branched-chain amino acids (BCAAs). The genes BCKDHA, BCKDHB, DBT, and DLD encode the subunits of Show more
Maple syrup urine disease (MSUD) is a rare inborn error of metabolism caused by impaired catabolism of branched-chain amino acids (BCAAs). The genes BCKDHA, BCKDHB, DBT, and DLD encode the subunits of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which is essential for BCAA metabolism. Catalytic subunits are BCKDHA, BCKDHB, DBT, and DLD, whereas the regulator subunits are PPM1K and BCKDK. PPM1K plays a critical role by dephosphorylating and activating this enzyme complex. Pathogenic variants in the PPM1K gene cause an extremely rare, mild form of MSUD. Here, we report an 8-year-old male patient with a mild form of MSUD putatively caused by a novel homozygous variant in PPM1K. The patient presented with mild dysmorphic features, delayed speech, relative microcephaly, and overweight, all considered familial phenotypic traits. Laboratory findings revealed mildly elevated plasma branched-chain amino acids, mild lactic acidemia, and a slight increase in urinary keto acids. Exome sequencing identified a novel homozygous missense variant, c.925A>G p.(Ile309Val), in the PPM1K gene. This case represents the third reported patient with a mild form of MSUD associated with the first reported missense variant in the PPM1K gene in the literature, further expanding the clinical and genetic spectrum of PPM1K-related disorders. Show less
HERC1 is a member of HERC protein family of ubiquitin ligases and is a negative regulator of the mTOR pathway. It is also a guanine nucleotide exchange factor for ARF and Rab family GTPases. Biallelic Show more
HERC1 is a member of HERC protein family of ubiquitin ligases and is a negative regulator of the mTOR pathway. It is also a guanine nucleotide exchange factor for ARF and Rab family GTPases. Biallelic mutations in HERC1 were recently shown to cause a human phenotype with overgrowth and intellectual disability as main features. Herein we describe clinical features in another patient with homozygous novel mutation in HERC1. Moderate to severe intellectual disability, hypotonia, macrocephaly, tall stature, and facial features appear as main clinical features of the condition. Kyphoscoliosis and seizures frequently accompany and autistic features might be another feature as recent studies also implicate. HERC1 mutations should be considered in differential diagnosis of severe intellectual disability and behavioural problems, particularly in patients testing negative for fragile X and KANSL1 mutations. Show less